Lilly became the first company to start testing an anti-SARS-CoV-2 antibody in humans at the start of June. Over the following weeks, Regeneron Pharmaceuticals moved a rival candidate into the clinic and AstraZeneca outlined plans to start testing its COVID-19 antibody asset in humans by August.
The flurry of activity showed Lilly is taking a different approach to the task of developing an antibody treatment for COVID-19. Regeneron combined its two most potent, non-competing virus-neutralizing antibodies into a single therapy in the belief it is necessary to attack the coronavirus from two angles to prevent the emergence of mutant, drug-resistant forms of the pathogen.
AstraZeneca is taking a similar two-antibody approach. Lilly, in contrast, is testing a single antibody in its clinical trials, putting it out of step with its peers.
Daniel Skovronsky, chief scientific officer at Lilly, explained the decision to choose the single-antibody candidate LY-CoV555 on a second quarter results conference call with investors.
“If you have one antibody, you can manufacture twice as much as a combo of two antibodies, three times as much as three antibodies. In a situation like this, I think there's societal trade-offs that might indicate maximizing manufacturing capacity is a key objective,” said Skovronsky.
Demand for an effective anti-SARS-CoV-2 antibody product, which could potentially be used to both treat and prevent COVID-19, is likely to be very high. In choosing a single-antibody regimen, Lilly has positioned itself to get more doses out of its manufacturing capacity.
The approach carries risks, though. Regeneron, the developer of an effective anti-Ebola antibody, opted to take a cocktail COVID-19 candidate into the clinic in light of concerns about the potential for the virus to develop resistance.
Antibody developers are trying to target epitopes that will be conserved even as the virus mutates, thereby ensuring their treatments remain effective. However, the strong selection pressure applied by a single therapeutic antibody could still drive the emergence of resistant strains.
In preclinical tests, Regeneron found viral escape mutants appeared rapidly when a surrogate for the pandemic coronavirus was exposed to individual antibodies. Regeneron mitigated that concern by including two antibodies that target different parts of the virus’ receptor binding domain.
The coronavirus would need to simultaneously mutate at two distinct genetic sites to escape from Regeneron’s cocktail. Such a simultaneous mutation is an unlikely, albeit theoretically possible, event.
Lilly acknowledges the potential for the virus to develop resistance to a single antibody. However, Skovronsky said data generated on LY-CoV555 so far suggests Lilly’s single-antibody approach may pay off.
“I think the extremely high potency of 555 and its ability to effectively neutralize virus very, very quickly may decrease the risk of resistance. We've done some primate studies and we've not seen resistance emerge in those studies at all,” said the Lilly executive.
Even so, Lilly is monitoring patients for signs of resistance and has a combination it can take forward if needed. The proposed combination would feature LY-CoV555, which Lilly licensed from AbCellera, and a second clinical-phase anti-SARS-CoV-2 antibody from a collaboration with Junshi Biosciences.